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In vivo and in vitro demonstration of herb-drug interference in human breast cancer cells treated with tamoxifen and trastuzumab

Chen, Jiun-Liang MD1,2,3; Wang, Jir-You PhD4; Tsai, Yi-Fang MD5; Lin, Yi-Hsien MD, PhD6,7; Tseng, Ling-Ming MD5,8; Chang, Wen-Chi MS9; King, Kuan-Liang MD5; Chen, Wei-Shone MD, PhD10,11; Chiu, Jen-Hwey MD, PhD1,5,12; Shyr, Yi-Ming MD5

Menopause:
doi: 10.1097/gme.0b013e31827b2240
Original Articles
Abstract

Objective: In recent trends, patients with breast cancer seek integrative medical treatment when receiving either hormonal (tamoxifen [Tam]) or target (trastuzumab) therapy. Our previous in vitro studies demonstrated that the Chinese medicine Si-Wu-Tang (SWT) stimulates MCF-7 cell growth via activation of estrogen receptor α and human epidermal growth factor receptor 2 (HER2) signaling. The present study demonstrates herb-drug interference with cell proliferation in tumor-bearing mice treated with SWT and Tam in vivo and with proliferation capacity in breast cancer cells treated with SWT and trastuzumab in vitro.

Methods: To assess in vivo SWT + Tam interference, we randomly separated female MCF-7–implanted athymic nude mice into five groups, namely, vehicle (n = 11), estradiol (n = 8), SWT (n = 8), Tam (n = 11), and SWT + Tam (n = 8). All mice were killed after 21 days of treatment. Body weight, uterine weight, tumor volume, and tumor weight were measured. To assess in vitro SWT-trastuzumab interference, we cotreated BT-474 and SK-BR-3 breast cancer cells with SWT and trastuzumab. This was followed by (4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays and cell cycle analysis to measure cell proliferation and by Western blot analysis to analyze protein expression in growth-related signal pathways.

Results: SWT reversed Tam-induced antiproliferative effects on tumor weight and tumor volume and increased estrogen receptor α and N-cadherin expression in the SWT + Tam–treated group compared with the Tam-treated group. Furthermore, SWT reversed trastuzumab-induced antiproliferative activity in HER2+ cell lines (SK-BR-3 and BT-474) through increased phosphorylation of the cell cycle regulatory protein p27(Kip1) and possibly of the antiapoptosis protein P38.

Conclusions: Based on the in vivo and in vitro demonstration of herb-drug interference in breast cancer cells, we conclude that physicians should pay more attention to such interference when treating patients with receptor-positive (estrogen receptor–positive, progesterone receptor–positive, or HER2+) breast cancers.

Author Information

From the 1Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; 2School of Traditional Chinese Medicine, Chang-Gung University, Taoyuan, Taiwan, ROC; 3Center for Traditional Chinese Medicine, Chang-Gung Memorial Hospital, Taoyuan, Taiwan, ROC; 4Department of Orthopedics, and 5Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; 6School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; 7Division of Radiotherapy, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; 8Department of Surgery, School of Medicine, and 9Laboratory Animal Center, National Yang-Ming University, Taipei, Taiwan, ROC;10Division of Colorectal Surgery, Department of Surgery, and 11Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; and 12Division of General Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC.

Received August 3, 2012; revised and accepted October 18, 2012.

L.-M.T. and J.-H.C. contributed equally to this work.

J.-H.C. and J.-Y.W. designed the experiments, performed data analysis and statistics, and drafted the manuscript. J.-L.C. and W.-C.C. participated in the design of the experiments and carried out the in vivo and in vitro experiments. L.-M.T. participated in the study design and helped with data analysis. Y.-F.T., Y.-H.L., K.-L.K., W.-S.C., and Y.-M.S. helped with data analysis and statistics. All authors read and approved the final manuscript.

Funding/support: This work was carried out with the assistance of the Division of Experimental Surgery, Department of Surgery, Taipei Veterans General Hospital. This work was supported by grants from the Taipei Veterans General Hospital (V100D-005-2), the Cheng-Hsin and Yang-Ming Project (100F117CY29), and the Chang-Gung Memorial Hospital (PMRPG3A0031).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Jen-Hwey Chiu, MD, PhD, or Ling-Ming Tseng, MD Institute of Traditional Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Peitou, Taipei 112, Taiwan, ROC. E-mail: chiujh@mailsrv.ym.edu.tw

© 2013 by The North American Menopause Society.